Gliomas are the most common primary brain tumors ranging from benign low- grade astrocytomas to highly malignant glioblastoma multiform. The classification of primary glial tumors reflecting their biological aggressiveness is based upon histopathologic characteristics. We have taken several approaches to understand and identify, at a molecular level, the underlying mechanisms that translate into the extremely malignant behavior of glioblastoma. 1. We have used x-chromosome inactivation analysis to study the clonal composition of glioblastomas. 2. The genomic organization of H-ras, N-ras, c-myc, bFGF, TGFalpha, TGFbeta, c-sis, c-erbB2, c-erbA2, and int-2 was analyzed and found to be normal in 20 primary tumors and 8 glioblastoma cell lines. 3. The transcription of bGFG, its surface-associated receptor, flg, TGFalpha, and TGFbeta, were generally elevated in most of the glioblastoma cell lines tested as compared to normal brain, an SV40 transformed human astroglial cell line, human breast cancer cell lines, a bladder carcinoma cell line, T24, and a hematopoietic cell line K562. An increased level of H-ras and c-myc protooncogenes was observed in all human tumor cell lines examined, whereas c-erbB2 expression was relatively increased in breast cancer cell lines. 4. Recessive mutations that predispose to cancer are unmasked in several human cancers by the loss of normal alleles. Restriction fragment length Polymorphism analysis (RFLP) was used to compare the constitutional and tumor genotypes in a panel of 40 glioblastomas. Loss of heterozygosity of several markers on chromosomes 17 and 10 was detected in a significant number of glioblastoma multiforme. Deletion mapping studies were carried out to more precisely define the position of the gene(s) on chromosome 17 whose deletion is probably important in the genesis of these tumors. 5. Six matched pairs of primary and recurrent tumors were analyzed for allelic deletions on chromosomes lO and l7. The data clearly demonstrated additional genetic abnormalities in recurrent tumors.